The long-term goal of this proposal is to understand the multiple roles that the Notch signaling pathway plays during embryonic development in mammals, and the connections between this pathway and the development of congenital human disease syndromes. The components of the Notch signaling pathway are essential for proper embryonic development in numerous organisms, and mutations in Notch pathway genes cause several inherited human disease syndromes. In mammals, four Notch family receptors have been described, encoded by the Notch1 - Notch4 genes. Notch receptors interact with membrane-bound ligands that are encoded by the Jagged (Jag1 and Jag2) and Delta-like (Dlll, Dll3, and Dll4) gene families. We have been performing a comprehensive genetic analysis of the requirements for Notch pathway components during embryonic development in mice. The aims of this proposal are to: 1) determine the role of the Dll4 gene and of other Notch pathway components in the development of the cardiovascular system; 2) test whether the PDZ Iigand domains at the carboxy termini of the JAG1 and DLL4 proteins are essential for function; 3) test whether the intracellular domains of the four different Notch receptors transmit equivalent signals by constructing single copy conditional gain of function alleles at the same genetic locus; 4) test whether Notch signaling plays an evolutionarily-conserved role during oocyte development. These studies will further our understanding of the roles of the Notch signaling pathway in mammalian development, and will be applicable to the study of both normal development and birth defects in humans.